We study persons who have an exceptionally high risk of cancer to find explanations for their susceptibility. These unusual individuals are identified through referral bY practitioners and by our own clinical observations at the bedside. With informed consent, epidemiologic inquiries are made to identify predisposing host and environmental factors, and to quantify the risk of cancer development. Results show that carriers of cancer genes develop cancer at high rates in specific tissues, including multiple primary cancers in childhood. Concurrent laboratory studies are made to clarify biologic mechanisms of cancer susceptibility. In the dominantly inherited syndrome of breast cancer, sarcomas and other childhood neoplasms (Li-Fraumeni family cancer syndrome), the inherited cancer susceptibility was shown to be due to the p53 gene. All 5 families with Li-Fraumeni syndrome that were examined had a germ line point mutation in the p53 gene. Work is in progress to map several other tumor suppressor genes, including genes for renal carcinomas and familial Wilms' tumor. In another study, nearly 1000 patients are under surveillance for the occurrence of second cancers through the Registry of Survivors of Childhood Cancer in Boston. An additional series of 1600 survivors of childhood retinoblastoma in New York and Boston have shown that the subgroup with hereditary retinoblastoma have a 50-fold increase in risk of second cancers, particularly sarcomas, brain tumors and melanoma.